JP2022534794A - Compositions and methods for treating pain in subjects with rheumatoid arthritis - Google Patents

Abstract

The present disclosure relates to the use of anti-IL6 receptor antibodies to treat excruciating pain in subjects with rheumatoid arthritis. A subject with intolerable pain can have, for example, intractable pain or severely intractable pain.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is filed June 4, 2019, U.S. Provisional Patent Application Serial No. 62/857,247; 966, and European Patent Application No. 20305191.7 filed February 27, 2020, the entire disclosure of which is hereby incorporated herein by reference.

The present disclosure relates to the field of therapeutic treatment of excruciating pain in subjects who have had or currently have rheumatoid arthritis.

Pain is a core-set domain and distressing symptom for patients with rheumatoid arthritis (RA) and can be directly associated with inflammation. Unbearable pain (UP) levels can be protracted or refractory pain (RP) in patients despite receiving treatment-induced inflammation control (IC).

Sarilumab is an interleukin for the treatment of adults with moderately to severely active RA who are inadequately responsive or intolerant to one or more disease-modifying antirheumatic drugs (DMARDs). -6 receptor antagonist.

The present disclosure presents methods and compositions for treating excruciating pain in subjects with rheumatoid arthritis. In various embodiments, treating a subject comprises administering a therapeutically effective amount of an antibody that specifically binds IL-6R.

In various embodiments, an antibody that specifically binds to the IL-6 receptor comprises the heavy chain variable region sequence of SEQ ID NO:1 and the light chain variable region sequence of SEQ ID NO:2.

In various embodiments, the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), VH comprising the three complementarity determining regions (CDRs) found within the sequence of SEQ ID NO: 1, and VL contains the three CDRs found within the sequence of SEQ ID NO:2. In various embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises three HCDRs (i.e., HCDR1, HCDR2 and HCDR3) and three LCDRs (i.e., LCDR1, LCDR2 and LCDR3), wherein HCDR1 is SEQ ID NO: 3, HCDR2 comprises the amino acid sequence of SEQ ID NO:4, HCDR3 comprises the amino acid sequence of SEQ ID NO:5, LCDR1 comprises the amino acid sequence of SEQ ID NO:6, and LCDR2 comprises the amino acid sequence of SEQ ID NO:7. , LCDR3 comprises the amino acid sequence of SEQ ID NO:8.

In various embodiments, the antibody is sarilumab.

In various embodiments, the subject has intractable pain. In various embodiments, the subject has UP despite controlling treatment-induced inflammation. In various embodiments, the subject has at least about 10%, 15%, 20%, 25%, 30%, 35%, 40% inflammation compared to when the subject was first treated with a DMARD. , 45%, or 50% lower UP. In various embodiments, the subject has 10%-25%, 25%-50%, 50%-75%, 75%-95% inflammation compared to when the subject was first treated with a DMARD. %, or 75% to 100% lower but still have UP. In various embodiments, the subject has at least about 10%, 15%, 20%, 25% inflammation compared to when the subject was initially treated with one or more DMARDs other than sarilumab , 30%, 35%, 40%, 45%, or 50% lower UP. In various embodiments, the subject has 10% to 25%, 25% to 50%, 50% to 25% inflammation compared to when the subject was treated with one or more DMARDs other than sarilumab. Have UP despite being 75%, 75%-95%, or 75%-100% lower. In various embodiments, the subject has strict refractory pain. In various embodiments, the subject experiences a reduction to less than 40 on a visual analogue scale (VAS) after 24 weeks or 52 weeks of treatment.

In various embodiments, the antibody is administered subcutaneously. In various embodiments, the antibody is administered every week or every two weeks. In various embodiments, the antibody is administered once a week or once every two weeks.

In various embodiments, the antibody is administered at a dose of about 150mg-200mg. In various embodiments, the antibody is administered at a dose of about 150 mg or about 200 mg. In various embodiments, the antibody is administered at a dose of 150mg-200mg. In various embodiments, the antibody is administered at a dose of 150 mg or 200 mg.

In various embodiments, the subject has rheumatoid arthritis. In various embodiments, the subject has moderately to severely active rheumatoid arthritis. In various embodiments, the subject has moderately active rheumatoid arthritis. In various embodiments, the subject has severely active rheumatoid arthritis.

In various embodiments, the subject has a Disease Activity Score (DAS) of 3.2-5.1. In various embodiments, the subject has a DAS greater than 5.1. In various embodiments, the subject has a DAS of 3.2 or greater. In various embodiments, the subject has a DAS of 5-6, 5-7, 5-8, 5-9, 5-10, or 7.5-10. The DAS of interest can be readily calculated by one skilled in the art. A non-limiting description relating to DAS is presented in Fransen and van Riel (Clin Exp Rheumatol. 2005 Sep-Oct;23(5Suppl39):S93-9), the entire contents of which are incorporated herein by reference. Incorporate.

In various embodiments, other disease-modifying anti-rheumatic drugs (DMARDs) are not administered with the antibody. In various embodiments, at least one other DMARD is administered to the subject. In various embodiments, at least one other DMARD is administered to the subject concurrently or concurrently with the antibody. In various embodiments, the subject has previously been treated for rheumatoid arthritis by administering at least one DMARD that is different from the antibody without success. In various embodiments, the subject is intolerant to one or more DMARDs, or the subject is considered an unsuitable candidate for continued treatment with one or more DMARDs.

In various embodiments, the DMARD is an sDMARD. In various embodiments the DMARD is methotrexate. In various embodiments the DMARD is a TNF antagonist. In various embodiments, the TNF antagonist is selected from etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol.

In another aspect, a method of treating excruciating pain (UP) in a subject in need thereof comprising the steps of selecting a subject with rheumatoid arthritis and UP, and a treatment that specifically binds to the IL-6 receptor administering a super effective dose of the antibody to the subject.

In various embodiments, an antibody that specifically binds to the IL-6 receptor comprises the heavy chain variable region sequence of SEQ ID NO:1 and the light chain variable region sequence of SEQ ID NO:2.

In various embodiments, the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), VH comprising the three complementarity determining regions (CDRs) found within the sequence of SEQ ID NO: 1, and VL contains the three CDRs found within the sequence of SEQ ID NO:2. In various embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises three HCDRs (ie, HCDR1, HCDR2, and HCDR3) and three LCDRs (ie, LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:3; HCDR2 comprises the amino acid sequence of SEQ ID NO:4; HCDR3 comprises the amino acid sequence of SEQ ID NO:5; LCDR1 comprises the amino acid sequence of SEQ ID NO:6; LCDR3 comprises the amino acid sequence of SEQ ID NO:8;

In various embodiments, the antibody is sarilumab.

In various embodiments, the subject has intractable pain. In various embodiments, the subject has treatment-induced severe, intractable pain. In various embodiments, the subject experiences a reduction to less than 40 on a visual analogue scale (VAS) after 24 weeks or 52 weeks of treatment.

In various embodiments, the antibody is administered subcutaneously. In various embodiments, the antibody is administered every week or every two weeks. In various embodiments, the antibody is administered once a week or once every two weeks.

In various embodiments, the antibody is administered at a dose of about 150mg-200mg. In various embodiments, the antibody is administered at a dose of about 150 mg or about 200 mg. In various embodiments, the antibody is administered at a dose of 150mg-200mg. In various embodiments, the antibody is administered at a dose of 150 mg or 200 mg.

In various embodiments, the subject has rheumatoid arthritis. In various embodiments, the subject has moderately to severely active rheumatoid arthritis. In various embodiments, the subject has moderately active rheumatoid arthritis. In various embodiments, the subject has severely active rheumatoid arthritis.

In various embodiments, other disease-modifying anti-rheumatic drugs (DMARDs) are not administered with the antibody. In various embodiments, at least one other DMARD is administered to the subject. In various embodiments, at least one other DMARD is administered to the subject concurrently or concurrently with the antibody. In various embodiments, the subject has previously been treated for rheumatoid arthritis by administering at least one DMARD that is different from the antibody without success. In various embodiments, the subject is intolerant to one or more DMARDs, or the subject is considered an unsuitable candidate for continued treatment with one or more DMARDs.

In various embodiments, the DMARD is an sDMARD. In various embodiments the DMARD is methotrexate. In various embodiments the DMARD is a TNF antagonist. In various embodiments, the TNF antagonist is selected from etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol.

In a further aspect, provided herein is an antibody for use in treating intolerable pain in a patient with rheumatoid arthritis in need thereof, said antibody specifically binding to the IL-6 receptor be done.

In various embodiments, an antibody that specifically binds to the IL-6 receptor comprises the heavy chain variable region sequence of SEQ ID NO:1 and the light chain variable region sequence of SEQ ID NO:2.

In various embodiments, the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), VH comprising the three complementarity determining regions (CDRs) found within the sequence of SEQ ID NO: 1, and VL contains the three CDRs found within the sequence of SEQ ID NO:2. In various embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises three HCDRs (ie, HCDR1, HCDR2, and HCDR3) and three LCDRs (ie, LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:3; HCDR2 comprises the amino acid sequence of SEQ ID NO:4; HCDR3 comprises the amino acid sequence of SEQ ID NO:5; LCDR1 comprises the amino acid sequence of SEQ ID NO:6; LCDR3 comprises the amino acid sequence of SEQ ID NO:8;

In various embodiments, the antibody is sarilumab.

In various embodiments, the subject has intractable pain. In various embodiments, the subject has treatment-induced severe, intractable pain. In various embodiments, the subject experiences a reduction to less than 40 on a visual analogue scale (VAS) after 24 weeks or 52 weeks of treatment.

In various embodiments, the antibody is administered subcutaneously. In various embodiments, the antibody is administered every week or every two weeks. In various embodiments, the antibody is administered once a week or once every two weeks.

In various embodiments, the antibody is administered at a dose of about 150mg-200mg. In various embodiments, the antibody is administered at a dose of about 150 mg or about 200 mg. In various embodiments, the antibody is administered at a dose of 150mg-200mg. In various embodiments, the antibody is administered at a dose of 150 mg or 200 mg.

In various embodiments, the subject has rheumatoid arthritis. In various embodiments, the subject has moderately to severely active rheumatoid arthritis. In various embodiments, the subject has moderately active rheumatoid arthritis. In various embodiments, the subject has severely active rheumatoid arthritis.

In various embodiments, the subject has a Disease Activity Score (DAS) of 3.2-5.1. In various embodiments, the subject has a DAS greater than 5.1. In various embodiments, the subject has a DAS of 3.2 or greater. In various embodiments, the subject has a DAS of 5-6, 5-7, 5-8, 5-9, 5-10, or 7.5-10. The DAS of interest can be readily calculated by one skilled in the art. A non-limiting description relating to DAS is presented in Fransen and van Riel (Clin Exp Rheumatol. 2005 Sep-Oct;23(5Suppl39):S93-9), the entire contents of which are incorporated herein by reference. Incorporate.

In various embodiments, other disease-modifying anti-rheumatic drugs (DMARDs) are not administered with the antibody. In various embodiments, at least one other DMARD is administered to the subject. In various embodiments, at least one other DMARD is administered to the subject concurrently or concurrently with the antibody. In various embodiments, the subject has previously been treated for rheumatoid arthritis by administering at least one DMARD that is different from the antibody without success. In various embodiments, the subject is intolerant to one or more DMARDs, or the subject is considered an unsuitable candidate for continued treatment with one or more DMARDs.

In various embodiments, the DMARD is an sDMARD. In various embodiments the DMARD is methotrexate. In various embodiments the DMARD is a TNF antagonist. In various embodiments, the TNF antagonist is selected from etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol.

FIGS. 1A-1C are graphs depicting odds ratios for three different randomized clinical trials—MOBILITY, TARGET, and MONARCH. FIG. 1A illustrates the odds ratio for intolerable pain. FIG. 1B illustrates the odds ratio for having intolerable pain despite inflammation control (IC) or inflammation control-intact (IC-intact). FIG. 1C illustrates the odds ratio for intractable pain-strict. Continuation of Figure 1-1. 2A-2C are graphs representing descriptive analyzes of pain outcomes. Figure 2A illustrates the analysis of pain outcomes in MOBILITY (weeks 24 and 52). Figure 2B illustrates the analysis of pain outcomes on TARGET (weeks 24 and 52). Figure 2C illustrates analysis of pain outcomes in MONARCH (weeks 24 and 52). Continuation of Figure 2-1.

The present disclosure provides pharmaceutical compositions and methods of using these compositions for treating intolerable pain (UP) levels. In some embodiments, UP persists despite inflammatory control (IC). In some embodiments, IC is induced by biologic therapy. These compositions and methods comprise at least one antibody that specifically binds to interleukin-6 receptor (hIL-6R).

The term "about" when used in the claims and in the Summary of the Invention, Detailed Description herein, in quantitative terms means plus or minus 10% of the value to be modified (that value is not divisible). (rounded to the nearest whole number, such as the number of molecules or nucleotides). For example, the phrase "about 100 mg" includes 90 mg to 110 mg, inclusive, and the phrase "about 2500 mg" includes 2250 mg to 2750 mg. When applied to percentages, the term “about” refers to plus or minus 10% relative to that percentage. For example, the phrase "about 20%" includes 18-22%, and "about 80%" includes 72-88%, inclusive. Further, when "about" is used herein with a quantitative term, it is understood that the exact value of the quantitative term is contemplated and described in addition to the value plus or minus 10%. For example, the term "about 23%" intends, describes and includes exactly 23%.

The term "a" or "an" entity refers to one or more of that entity, e.g., "a symptom" is understood to represent one or more symptoms. Note that As such, the terms "a" (or "an"), "one or more", and "at least one" can be used interchangeably herein.

Moreover, as used herein, “and/or” is to be interpreted as specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and/or" as used herein in phrases such as "A and/or B" means "A and B", "A or B", "A" (alone) and "B" intended to include (alone) Similarly, the term "and/or" when used in phrases such as "A, B, and/or C" refers to the following aspects: A, B, and C; A, B, or C; A or B; B or C; A and C; A and B; B and C; A (alone);

Although any aspect is described herein in the language of "comprising," the terms "consisting of" and/or "consisting essentially of" It is understood that other similar embodiments described in are also provided.

The term "pain" refers to discomfort caused by an intense or damaging stimulus, including disease, injury, or psychiatric distress. In some embodiments, pain is experienced as an unpleasant sensation that has both physical and emotional components and can range from mild localized discomfort to severe pain.

The term "unbearable pain" refers to the level expressed by the patient acceptable symptom state (PASS), a validated measure of the level of tolerable pain. PASS uses a threshold of 40 mm on the visual analogue scale (VAS) ranging from 0 to 100 mm, meaning that VAS>40 mm represents intolerable pain. Ｌｏｕｒｄｕｄｏｓｓら（Ｄｉｅｔａｒｙ ｉｎｔａｋｅ ｏｆ ｐｏｌｙｕｎｓａｔｕｒａｔｅｄ ｆａｔｔｙ ａｃｉｄｓ ａｎｄ ｐａｉｎ ｉｎ ｓｐｉｔｅ ｏｆ ｉｎｆｌａｍｍａｔｏｒｙ ｃｏｎｔｒｏｌ ａｍｏｎｇ ｍｅｔｈｏｔｒｅｘａｔｅ－ｔｒｅａｔｅｄ ｅａｒｌｙ ｒｈｅｕｍａｔｏｉｄ ａｒｔｈｒｉｔｉｓ ｐａｔｉｅｎｔｓ．Ａｒｔｈｒｉｔｉｓ Ｃａｒｅ ａｎｄ Ｒｅｓｅａｒｃｈ．２０１８；７０（２）：２０５－２１２）；ならびにＰｈａｍおよびＴｕｂａｃｈ（Ｐａｔｉｅｎｔ ａｃｃｅｐｔａｂｌｅ ｓｙｍｐｔｏｍａｔｉｃ state (PASS).Joint Bone Spine 2009;76:321-3), each of which is hereby incorporated by reference in its entirety. In some embodiments, pain experienced in the previous week is measured. In some embodiments, pain experienced 2, 3, 4, 5, 6, 7, 8 or more weeks back is measured. In some embodiments, pain experienced one month prior is measured. In some embodiments, pain experienced 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or longer months is measured. In some embodiments, pain experienced one year ago is measured. In some embodiments, pain experienced 2, 3, 4, 5, 6, 7, 8, 9, 10 years or more years back is measured.

Subjects experiencing "refractory pain" have rheumatoid arthritis, excruciating pain, and serum levels of C-reactive protein (CRP) less than 10 mg/mL. Subjects experiencing "severe intractable pain" have rheumatoid arthritis, excruciating pain, a swollen joint count (SJC) of 1 or less, and serum levels of CRP less than 10 mg/mL. In some embodiments, the rheumatoid arthritis is moderately to severely active rheumatoid arthritis.

IL-6 interacts directly with the IL-6Rα subunit and the IL-6/IL-6Rα pair forms a high affinity complex with the glycoprotein 130 (gp130) subunit. IL-6Rα also exists in a soluble form, which is involved in trans-signaling, allowing IL-6 to affect cells that do not express IL-6Rα, including synoviocytes within joints. (Rose-John et al., J Leukoc Biol. 2006; 80(2), 227-36). Sarilumab (SAR153191), also called REGN88, is a fully human sequence recombinant IgG1 kappa monoclonal antibody directed against the alpha subunit (IL-6Rα) of the IL-6 receptor complex. Sarilumab is a potent and specific inhibitor of IL-6 signaling. By binding IL-6Rα with high affinity, sarilumab blocks IL-6 binding and disrupts cytokine-mediated signaling cascades. In certain embodiments, interleukin-6 is a key factor in the pathogenesis of rheumatic conditions and inhibition of its signaling is an important part of sarilumab's mechanism of action. In in vivo assays, sarilumab did not exhibit antibody dependent cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC) against relevant cell types. Here, sarilumab binding was determined by fluorescence-activated cell sorting (FACS) analysis (Commission for Medicinal Products for Human Use, Assessment Report available at www_dot_ema_dot_europa_dot_eu/documents/assessment_report/kevzara_epar_public_assessment_report_en_dot_pdf, April 27, 2017 EMA/292840/2017). Verified.

Antibodies The present disclosure includes methods comprising administering to a subject an antibody or antigen-binding fragment thereof that specifically binds to hIL-6R. As used herein, the term "hIL-6R" means a human cytokine receptor that specifically binds human interleukin-6 (IL-6). In certain embodiments, the antibody administered to the patient specifically binds to the extracellular domain of hIL-6R.

The term "antibody" as used herein includes four polypeptide chains, two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, and multimers thereof ( For example, it refers to immunoglobulin molecules, including IgM). Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region contains three domains CH1, CH2 and CH3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region contains one domain (CL1). The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of an antibody (or antigen-binding portion thereof) can be identical to human germline sequences, or are naturally or artificially modified. An amino acid consensus sequence can be defined based on parallel analysis of two or more CDRs.

The term "antibody" as used herein also includes antigen-binding fragments of full antibody molecules. The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, etc., as used herein, refer to any naturally occurring enzyme that specifically binds to an antigen to form a complex. It includes synthetic or genetically engineered polypeptides or glycoproteins obtained commercially. Antigen-binding fragments of antibodies may be prepared, e.g., whole antibodies, using any suitable standard technique, such as proteolytic digestion or recombinant genetic engineering techniques, including manipulation and expression of the DNA encoding the antibody variable and, optionally, constant domains. It can be derived from molecules. Such DNAs are known and/or readily available, eg, from commercial sources, DNA libraries (including, eg, phage-antibody libraries), or can be synthesized. The DNA is modified, for example, to arrange one or more variable and/or constant domains in proper configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids. It can be sequenced and manipulated chemically or using molecular biology techniques to eliminate it.

(ii) F(ab′)2 fragment; (iii) Fd fragment; (iv) Fv fragment; (v) single-chain Fv (scFv (vi) a dAb fragment; and (vii) a minimal recognition unit (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide) consisting of amino acid residues that mimics the hypervariable regions of an antibody, or Constrained FR3-CDR3-FR4 peptides are included. Also other engineered molecules such as domain specific antibodies, single domain antibodies, domain deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies). and bivalent nanobodies), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains are encompassed by the term "antigen-binding fragment" as used herein.

An antigen-binding fragment of an antibody typically comprises at least one variable domain. A variable domain can be of any size or amino acid composition and generally comprises at least one CDR that is flanked by or in-frame with one or more framework sequences. In antigen-binding fragments having a VH domain associated with a VL domain, the VH and VL domains are arranged relative to each other in any suitable arrangement. For example, the variable region is dimeric and can include VH-VH, VH-VL or VL-VL dimers. Alternatively, an antigen-binding fragment of an antibody may comprise a monomeric VH or VL domain.

In certain embodiments, an antigen-binding fragment of an antibody may comprise at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of the variable and constant domains found within an antigen-binding fragment of an antibody are: (i) VH-CH1; (ii) VH-CH2; (iii) VH-CH3; (v) VH-CH1-CH2-CH3; (vi) VH-CH2-CH3; (vii) VH-CL; (viii) VL-CH1; (ix) VL-CH2; (x) VL- (xi) VL-CH1-CH2; (xii) VL-CH1-CH2-CH3; (xiii) VL-CH2-CH3; and (xiv) VL-CL. In any configuration of the variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains are directly linked to each other or by a complete or partial hinge or linker region. The hinge regions are, in various embodiments, at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids. Further, antigen-binding fragments of antibodies, in various embodiments, are non-covalently linked (e.g., via disulfide bonds) to each other and/or to one or more of the monomeric VH or VL domains listed above. It may comprise homodimers or heterodimers (or other multimers) of either variable and constant domain configurations.

In certain embodiments, antibodies or antibody fragments for use in the methods disclosed herein can be monospecific antibodies. In certain embodiments, antibodies or antibody fragments for use in the methods disclosed herein can be specific for different epitopes of one target polypeptide, or can target more than one target. It can be a multispecific antibody, which can contain antigen binding domains specific for epitopes of the polypeptide. An exemplary bispecific antibody format that can be used in connection with certain embodiments involves the use of a first immunoglobulin (Ig) C _H3 domain and a second IgC _H3 domain, wherein the first and The second IgC _H3 domains differ from each other by at least one amino acid, and the at least one amino acid difference reduces binding of the bispecific antibody to Protein A compared to a bispecific antibody lacking the amino acid difference. In one embodiment, the first Ig C _H3 domain binds Protein A and the second Ig C _H3 domain reduces or reduces Protein A binding, such as an H95R modification (by IMGT exon numbering; H435R by EU numbering). Contains deletion mutations. The second CH3 can further comprise a _Y96F modification (by IMGT; Y436F by EU). Additional modifications found within the second CH3 include, for IgG1 antibodies, _D16E , L18M, N44S, K52N, V57M and V82I (by IMGT; D356E, L358M, N384S, K392N, V397M and V422I by EU); For antibodies N44S, K52N and V82I (IMGT; N384S, K392N and V422I by EU); and for IgG4 antibodies Q15R, N44S, K52N, V57M, R69K, E79Q and V82I (by IMGT; K392N, V397M, R409K, E419Q and V422I). Variations on the bispecific antibody formats described above are contemplated within the scope of certain embodiments. Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, can be prepared, in various embodiments, by anti-IL-antibody using routine techniques available in the art. It is adapted for use in connection with antigen-binding fragments of 6R antibodies.

The fully human anti-IL-6R antibodies disclosed herein have one or more amino acids in the framework and/or CDR regions of the heavy and light chain variable domains compared to the corresponding germline sequences. It may contain substitutions, insertions and/or deletions. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available, for example, from public antibody sequence databases. The disclosure includes antibodies and antigen-binding fragments thereof derived from any of the amino acid sequences disclosed herein, wherein in one or more framework and/or CDR regions, one or more Amino acids are backmutated to the corresponding germline residue(s) or conservative amino acid substitutions (natural or non-natural) of the corresponding germline residue(s) (such sequence alterations are , referred to herein as "germline backmutation"). Starting from the heavy and light chain variable region sequences disclosed herein, one skilled in the art will have the ability to develop a large number of antibody and antigen-binding sequences comprising one or more individual germline backmutations or combinations thereof. Fragments can be easily generated. In certain embodiments, all of the framework residues and/or CDR residues within the VH and/or VL domains are backmutated to the germline sequence. In other embodiments, only certain residues are backmutated to the germline sequence, e.g., the mutated residues found within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4. only, or only mutated residues found within CDR1, CDR2 or CDR3. Furthermore, any combination of two or more germline backmutations within the framework and/or CDR regions can be included, i.e., certain individual residues are backmutated to germline sequences. Included herein are antibodies in which certain other residues that differ from the germline sequence are maintained, while others are retained. Once obtained, antibodies and antigen-binding fragments comprising one or more germline backmutations have improved binding specificity, increased binding affinity, improved antagonistic or agonistic biological properties. or can be readily tested for one or more desired properties, such as enhancement (optionally), reduced immunogenicity, and the like. Antibodies and antigen-binding fragments obtained by this general method are encompassed by the present disclosure.

The constant region of an antibody is important in the ability of the antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, the isotype of the antibody is selected based on whether it is desirable for the antibody to mediate cytotoxicity. The term "human antibody", as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies featured in this disclosure are, in various embodiments, nevertheless produced by amino acid residues not encoded by human germline immunoglobulin sequences (e.g., by random or site-directed mutagenesis in vitro or in vivo). mutations introduced by somatic mutation in ), for example CDRs and in some embodiments CDR3. However, the term "human antibody" as used herein is meant to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as mouse, have been grafted onto human framework sequences. Not intended.

The term "recombinant human antibody", as used herein, is intended to include all human antibodies prepared, expressed, produced or isolated by recombinant means, e.g., transfected into a host cell. antibodies expressed using recombinant expression vectors (described further below), antibodies isolated from recombinant combinatorial human antibody libraries (described further below), against human immunoglobulin genes Antibodies isolated from animals (eg, mice) that are transgenic (see, eg, Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295, which is incorporated herein by reference in its entirety). See also), or any other means that involve the splicing of the human immunoglobulin gene sequences into other DNA sequences, prepared, expressed, generated or isolated. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or in vivo somatic mutagenesis if animal transgenics for human Ig sequences are used), Thus, the amino acid sequences of the VH and VL regions of the recombinant antibody are derived from and related to human germline VH and VL sequences, with sequences that cannot be naturally occurring in vivo within the human antibody germline repertoire. be.

Human antibodies can exist in two forms related to hinge heterogeneity. In certain embodiments, the immunoglobulin molecule comprises a stable four-chain construct of about 150-160 kDa, and the dimers are held together by interchain heavy chain disulfide bonds. In another embodiment, the dimer is not linked via an interchain disulfide bond and the approximately 75-80 kDa molecule is composed of covalently linked light and heavy chains (half-antibodies). In certain embodiments, these forms were extremely difficult to separate, even after affinity purification.

The frequency of occurrence of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the antibody's hinge region isotype. Single amino acid substitutions in the hinge region of the human IgG4 hinge, to the level typically observed with the human IgG1 hinge, are of the second form (Angal et al. (1993) Molecular Immunology vol. 30, incorporated by reference in its entirety). : page 105) can be significantly reduced. The present disclosure, in various embodiments, encompasses antibodies with one or more mutations in the hinge, CH2 or CH3 regions, e.g., desirable to improve the yield of the desired antibody form in production. Sometimes.

By "isolated antibody" as used herein is meant an antibody that has been identified, separated and/or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism or from a tissue or cell in which it naturally occurs or is produced is an "isolated antibody." In various embodiments, isolated antibody also includes the antibody in situ within recombinant cells. In other embodiments, an isolated antibody is one that has been subjected to at least one purification or isolation step. In various embodiments, an isolated antibody can be substantially free of other cellular material and/or chemicals.

The terms "specifically bind" and the like mean that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, an antibody that "specifically binds" IL-6R as used herein is less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, as measured in a surface plasmon resonance assay less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM; Antibodies that bind IL-6R (eg, human IL-6R) or portions thereof with a KD of less than about 2 nM, less than about 1 nM, or about 0.5 nM. In some embodiments, the antibody binds IL-6R (eg, human IL-6Rα) with a KD of about 0.1 nM to about 1000 nM, or about 1 nM to about 100 nM. In some embodiments, the antibody binds IL-6R (eg, human IL-6Rα) with a KD of about 1 pM to about 100 pM, or about 40 pM to about 60 pM. Specific binding may also be characterized by a dissociation constant of at least about 1×10 ⁻⁶ M or less. In other embodiments, the dissociation constant is at least about 1×10 ⁻⁷ M, 1×10 ⁻⁸ M, or 1×10 ⁻⁹ M. An isolated antibody that specifically binds human IL-6R may, however, have cross-reactivity to other antigens, such as IL-6R molecules from other (non-human) species.

The term "surface plasmon resonance" as used herein refers to the detection of changes in protein concentration within a biosensor matrix using, for example, the BIACORE system (Biacore Life Sciences Division of GE Healthcare, Piscataway, NJ). Refers to an optical phenomenon whose detection allows the analysis of real-time interactions.

The term "KD", as used herein, is intended to refer to the equilibrium dissociation constant of the antibody-antigen interaction.

The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site within the variable region of an antibody molecule, known as the paratope. A single antigen can have more than one epitope. Thus, different antibodies can bind to different regions on the antigen and have different biological effects. Epitopes can be conformational or linear. Conformational epitopes are produced by spatially ordered amino acids from different segments of a linear polypeptide chain. A linear epitope is one that is produced by adjacent amino acid residues in a polypeptide chain. In certain situations, an epitope can include a sugar, phosphoryl, or sulfonyl moiety on an antigen.

Anti-IL-6R antibodies useful in the methods described herein, in various embodiments, have heavy and light chain variable domain frameworks and sequences relative to the corresponding germline sequences from which the antibodies are derived. /or may contain one or more amino acid substitutions, insertions and/or deletions in the CDR regions. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available, for example, from public antibody sequence databases. The present disclosure includes, in various embodiments, methods involving the use of antibodies and antigen-binding fragments thereof derived from any of the amino acid sequences disclosed herein, comprising one or more frameworks and/or or one or more amino acids in the CDR regions to the corresponding residue(s) of the germline sequence from which the antibody was derived, or to the corresponding residue(s) of another human germline sequence. or to conservative amino acid substitutions of the corresponding germline residue(s) (such sequence changes are collectively referred to herein as "germline mutations"). Multiple antibodies and antigen-binding fragments can be constructed that contain one or more individual germline mutations or combinations thereof. In certain embodiments, all of the framework and/or CDR residues within the VH and/or VL domains are backmutated to residues found within the germline sequence from which the antibody was derived. . In other embodiments, only certain residues are backmutated to the original germline sequence, e.g., found within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4. Only mutated residues found within CDR1, CDR2 or CDR3. In other embodiments, one or more framework and/or CDR residue(s) are in a different germline sequence (i.e., a different germline sequence than the germline sequence from which the antibody was originally derived). sequence) at the corresponding residue(s). Furthermore, an antibody may comprise any combination of two or more germline mutations in the framework and/or CDR regions, e.g. Certain different residues that are mutated to the corresponding residue while differing from the original germline sequence are either maintained or mutated to the corresponding residue in a different germline sequence. be. Once obtained, antibodies and antigen-binding fragments comprising one or more germline mutations may have improved binding specificity, increased binding affinity, improved antagonistic or agonistic biological properties or It can be readily tested for one or more desired properties such as enhancement (optionally), reduced immunogenicity, and the like. The use of antibodies and antigen-binding fragments obtained by this general method is encompassed by the present disclosure.

The disclosure also involves the use of anti-IL-6R antibodies comprising variants of any of the HCVR, LCVR and/or CDR amino acid sequences disclosed herein having one or more conservative substitutions. including methods. For example, the present disclosure makes conservative amino acid substitutions, e.g., 10 or less, 8 or less, 6 or less, 4 or less, etc. including the use of anti-IL-6R antibodies with HCVR, LCVR, and/or CDR amino acid sequences having

According to the present disclosure, the anti-IL-6R antibody or antigen-binding fragment thereof, in various embodiments, is an anti-IL-6R antibody, as described in US Pat. No. 7,582,298, herein incorporated by reference in its entirety. Includes heavy chain variable regions (HCVR), light chain variable regions (LCVR), and/or complementarity determining regions (CDR) comprising any of the antibody amino acid sequences. In certain embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (HCDR) of HCVR comprising the amino acid sequence of SEQ ID NO:1 and a LCVR comprising the amino acid sequence of SEQ ID NO:2. It contains a light chain complementarity determining region (LCDR). According to certain embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises three HCDRs (i.e., HCDR1, HCDR2 and HCDR3) and three LCDRs (i.e., LCDR1, LCDR2 and LCDR3); HCDR1 comprises the amino acid sequence of SEQ ID NO:3, HCDR2 comprises the amino acid sequence of SEQ ID NO:4, HCDR3 comprises the amino acid sequence of SEQ ID NO:5, LCDR1 comprises the amino acid sequence of SEQ ID NO:6, and LCDR2 comprises the amino acid sequence of SEQ ID NO:7. LCDR3 comprises the amino acid sequence of SEQ ID NO:8. In still other embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises an HCVR comprising the amino acid sequence of SEQ ID NO:1 and an LCVR comprising the amino acid sequence of SEQ ID NO:2.

In another embodiment, the anti-IL-6R antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10. In some embodiments, the extracellular domain of hIL-6R comprises the amino acid sequence of SEQ ID NO:11. According to certain exemplary embodiments, the methods of the present disclosure involve the use of an anti-IL-6R antibody known in the art, called sarilumab, or a bioequivalent thereof.

The amino acid sequence of SEQ ID NO: 1 is
EVQLVESGGGGLVQPGRSRLLSCAASRFTFDDYAMHWVRQAPGKGLEWVSGISWNSGRIGYADSVKGRFTISRDNAENSLFLQMNGLRAEDTALYYCAKGRDSFDIWGQGTMVTVSS
is.

The amino acid sequence of SEQ ID NO: 2 is
DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYGASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFASYYCQQANSFPYTFGQGTKLEIK
is.

The amino acid sequence of SEQ ID NO:3 is RFTFDDYA.

The amino acid sequence of SEQ ID NO: 4 is ISWNSGRI.

The amino acid sequence of SEQ ID NO: 5 is AKGRDSFDI.

The amino acid sequence of SEQ ID NO: 6 is QGISSW.

The amino acid sequence of SEQ ID NO:7 is GAS.

The amino acid sequence of SEQ ID NO:8 is QQANSFPYT.

The amino acid sequence of SEQ ID NO: 9 is
ＥＶＱＬＶＥＳＧＧＧＬＶＱＰＧＲＳＬＲＬＳＣＡＡＳ ＲＦＴＦＤＤＹＡ ＭＨＷＶＲＱＡＰＧＫＧＬＥＷＶＳＧ ＩＳＷＮＳＧＲＩ ＧＹＡＤＳＶＫＧＲＦＴＩＳＲＤＮＡＥＮＳＬＦＬＱＭＮＧＬＲＡＥＤＴＡＬＹＹＣ ＡＫＧＲＤＳＦＤＩ ＷＧＱＧＴＭＶＴＶＳＳＡＳＴＫＧＰＳＶＦＰＬＡＰＳＳＫＳＴＳＧＧＴＡＡＬＧＣＬＶＫＤＹＦＰＥＰＶＴＶＳＷＮＳＧＡＬＴＳＧＶＨＴＦＰＡＶＬＱＳＳＧＬＹＳＬＳＳＶＶＴＶＰＳＳＳＬＧＴＱＴＹＩＣＮＶＮＨＫＰＳＮＴＫＶＤＫＫＶＥＰＫＳＣＤＫＴＨＴＣＰＰＣＰＡＰＥＬＬＧＧＰＳＶＦＬＦＰＰＫＰＫＤＴＬＭＩＳＲＴＰＥＶＴＣＶＶＶＤＶＳＨＥＤＰＥＶＫＦＮＷＹＶＤＧＶＥＶＨＮＡＫＴＫＰＲＥＥＱＹＮＳＴＹＲＶＶＳＶＬＴＶＬＨＱＤＷＬＮＧＫＥＹＫＣＫＶＳＮＫＡＬＰＡＰＩＥＫＴＩＳＫＡＫＧＱＰＲＥＰＱＶＹＴＬＰＰＳＲＤＥＬＴＫＮＱＶＳＬＴＣＬＶＫＧＦＹＰＳＤＩＡＶＥＷＥＳＮＧＱＰＥＮＮＹＫＴＴＰＰＶＬＤＳＤＧＳＦＦＬＹＳＫＬＴＶＤＫＳＲＷＱＱＧＮＶＦＳＣＳＶＭＨＥＡＬＨＮＨＹＴＱＫＳＬＳＬＳＰＧＫ
is.

The amino acid sequence of SEQ ID NO: 10 is
ＤＩＱＭＴＱＳＰＳＳＶＳＡＳＶＧＤＲＶＴＩＴＣＲＡＳ ＱＧＩＳＳＷ ＬＡＷＹＱＱＫＰＧＫＡＰＫＬＬＩＹ ＧＡＳ ＳＬＥＳＧＶＰＳＲＦＳＧＳＧＳＧＴＤＦＴＬＴＩＳＳＬＱＰＥＤＦＡＳＹＹＣ ＱＱＡＮＳＦＰＹＴ ＦＧＱＧＴＫＬＥＩＫＲＴＶＡＡＰＳＶＦＩＦＰＰＳＤＥＱＬＫＳＧＴＡＳＶＶＣＬＬＮＮＦＹＰＲＥＡＫＶＱＷＫＶＤＮＡＬＱＳＧＮＳＱＥＳＶＴＥＱＤＳＫＤＳＴＹＳＬＳＳＴＬＴＬＳＫＡＤＹＥＫＨＫＶＹＡＣＥＶＴＨＱＧＬＳＳＰＶＴＫＳＦＮＲＧＥＣ
is.

The amino acid sequence of SEQ ID NO: 11 is
ＭＶＡＶＧＣＡＬＬＡＡＬＬＡＡＰＧＡＡＬＡＰＲＲＣＰＡＱＥＶＡＲＧＶＬＴＳＬＰＧＤＳＶＴＬＴＣＰＧＶＥＰＥＤＮＡＴＶＨＷＶＬＲＫＰＡＡＧＳＨＰＳＲＷＡＧＭＧＲＲＬＬＬＲＳＶＱＬＨＤＳＧＮＹＳＣＹＲＡＧＲＰＡＧＴＶＨＬＬＶＤＶＰＰＥＥＰＱＬＳＣＦＲＫＳＰＬＳＮＶＶＣＥＷＧＰＲＳＴＰＳＬＴＴＫＡＶＬＬＶＲＫＦＱＮＳＰＡＥＤＦＱＥＰＣＱＹＳＱＥＳＱＫＦＳＣＱＬＡＶＰＥＧＤＳＳＦＹＩＶＳＭＣＶＡＳＳＶＧＳＫＦＳＫＴＱＴＦＱＧＣＧＩＬＱＰＤＰＰＡＮＩＴＶＴＡＶＡＲＮＰＲＷＬＳＶＴＷＱＤＰＨＳＷＮＳＳＦＹＲＬＲＦＥＬＲＹＲＡＥＲＳＫＴＦＴＴＷＭＶＫＤＬＱＨＨＣＶＩＨＤＡＷＳＧＬＲＨＶＶＱＬＲＡＱＥＥＦＧＱＧＥＷＳＥＷＳＰＥＡＭＧＴＰＷＴＥＳＲＳＰＰＡＥＮＥＶＳＴＰＭＱＡＬＴＴＮＫＤＤＤＮＩＬＦＲＤＳＡＮＡＴＳＬＰＶＱＤ
is.

The term "bioequivalent", as used herein, refers to the same molar dosage and similar refers to molecules that have similar bioavailability (availability and degree of availability) after administration under conditions of (e.g., same route of administration). Two pharmaceutical compositions comprising an anti-IL-6R antibody are bioequivalent if they are pharmaceutically equivalent and because they meet the same or equivalent criteria for the same route of administration In addition, it means that the same dosage form contains the same amount of active ingredient (eg, IL-6R antibody). Bioequivalence can be determined, for example, by in vivo studies comparing the pharmacokinetic parameters of two compositions. Commonly used parameters in bioequivalence studies include maximum plasma concentration (Cmax) and area under the plasma drug concentration time curve (AUC).

The disclosure in certain embodiments relates to a method comprising administering to a subject an antibody comprising a heavy chain variable region comprising the sequence of SEQ ID NO:1 and a light chain variable region comprising the sequence of SEQ ID NO:2.

The disclosure provides pharmaceutical compositions comprising such antibodies, and methods of using these compositions.

The antibody in various embodiments comprises a heavy chain variable region comprising the sequence of SEQ ID NO:1 and a light chain variable region comprising the sequence of SEQ ID NO:2, and is specific for the human interleukin-6 receptor (hIL-6R). It is the antibody that binds. See WO2007/143168, which is incorporated herein by reference in its entirety. In one embodiment, the antibody comprises a heavy chain variable region comprising the sequence of SEQ ID NO:9 and a light chain variable region comprising the sequence of SEQ ID NO:10. In various embodiments, the antibody is sarilumab.

DMARD
Disease-modifying anti-rheumatic drugs (DMARDs) are drugs defined by their use to slow disease progression in rheumatoid arthritis. DMARDs have been classified as synthetic (sDMARD) and biological (bDMARD). Synthetic DMARDs include, non-exhaustively, methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine. Biological DMARDs include, non-exhaustively, adalimumab, golimumab, etanercept, abatacept, infliximab, rituximab, and tocilizumab. In some embodiments, DMARDs are TNF antagonists. TNF antagonists include etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol.

Methods of Administration and Formulations The methods described herein involve administering a therapeutically effective amount of an anti-IL-6R antibody to a subject. As used herein, an “effective amount” or “therapeutically effective amount” is the dose of therapeutic agent that results in treatment of intolerable pain (UP). In certain embodiments, an effective amount is a dose of therapeutic agent that results in treatment of protracted UP despite inflammation control (IC). As used herein, "treating" means causing a detectable amelioration of one or more symptoms associated with UP or causing an underlying disease causing the condition or symptom(s). Refers to causing a biological effect (eg, a decrease in the level of a particular biomarker) that correlates with a physical mechanism. For example, a dose of anti-IL-6R antibody that causes a decrease in UP is considered a "therapeutically effective amount."

"Amelioration" of pain-related symptoms is, in various embodiments, an improvement in pain symptoms that can be correlated with an improvement in one or more pain-related tests, scores, or metrics (described herein). Refers to a reduction in incidence. For example, improvement can be correlated with a decrease from baseline in one or more pain measures. In various embodiments, improvement can include a decrease from baseline in VAS. In various embodiments, the VAS baseline score is 40 mm or greater and decreases to a score of 40 mm or less. As used herein, the term "baseline," with respect to pain-related parameters, means the numerical values of pain-related parameters for a patient before or at the time of administration of an antibody of the invention. A detectable "improvement" can also be detected using at least one test, score or metric described herein. In various embodiments, improvement is detected using VAS. In various embodiments, improvement is characterized by its relationship to the subject's PASS status.

In various embodiments, prior treatment with a DMARD other than an anti-IL-6R antibody (such as sarilumab) was inadequate (e.g., according to subject and/or physician assessment) and had no effect; and/or did not cause a detectable improvement in one or more parameters or symptoms associated with pain and/or the underlying pathophysiological mechanism(s) causing the pain state or symptom(s) It did not cause correlating biological effects.

In various embodiments, the IL-6R antibody is administered subcutaneously. In various embodiments, the IL-6R antibody is sarilumab.

In various embodiments, the therapeutically effective amount of anti-IL-6R antibody administered to a subject depends on the subject's age and size (eg, weight or body surface area), as well as the route of administration and other factors well known to those of skill in the art. and change.

In various embodiments, the dose is a fixed dose regardless of subject weight or surface area. In various embodiments, the subject is at least 18 years old. In various embodiments, the subject is 30-100 years old. In various embodiments, the subject is 35-100 years old. In various embodiments, the subject is 35-8 years old. In various embodiments, the subject is 40-70 years old.

The present disclosure provides methods of using therapeutic compositions comprising an anti-IL-6R antibody or antigen-binding fragment thereof and optionally one or more additional therapeutic agents. The therapeutic compositions of the invention are administered with suitable carriers, excipients and/or other agents that are incorporated into formulations to provide improved migration, delivery, tolerance, and the like. Many suitable formulations are found in formulas known to all medicinal chemists, i.e., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, which is hereby incorporated by reference in its entirety. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipids (cationic or anionic) containing vesicles (e.g. lipofectins), DNA conjugates, anhydrous absorbent pastes, aqueous Included are oil and water-in-oil emulsions, emulsion carbowaxes (polyethylene glycols of various molecular weights), semisolid gels, and semisolid mixtures containing carbowaxes. See also Powell et al., "Compendium of excipients for parental formulations," PDA (1998) J Pharm Sci Technol 52:238-311, which is hereby incorporated by reference in its entirety.

Various delivery systems, such as liposomal encapsulation, microparticles, microcapsules, receptor-mediated endocytosis, are known and can be used to administer the pharmaceutical compositions presented herein (see, e.g., (1987) J. Biol. Chem. 262:4429-4432), which is incorporated herein by reference. Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural and oral routes. The compositions may be administered by any convenient route, including infusion or bolus injection, absorption through epithelial or mucocutaneous linings (eg, oral mucosa, rectal and intestinal mucosa, etc.), and other biological methods. It can be administered with an active agent. Administration can be systemic or local. IL-6R antibodies can be administered subcutaneously.

Pharmaceutical compositions can also be delivered in vesicles such as liposomes (see Langer (1990) Science 249:1527-1533, which is incorporated herein by reference in its entirety). In certain embodiments, pharmaceutical compositions can be delivered using controlled release systems, such as pumps or polymeric materials. In certain embodiments, the controlled release system can be placed near the target of the composition, thus requiring only a fraction of the systemic dosage.

Injectable formulations may include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injections, topical injections, infusion injections, and the like. These injection formulations can be prepared by known methods. For example, injectable preparations can be prepared by dissolving, suspending or emulsifying the antibody or a salt thereof in a sterile aqueous or oily medium commonly used for injection. Aqueous vehicles for injection include, for example, alcohols (eg, ethanol), polyalcohols (eg, propylene glycol, polyethylene glycol), nonionic surfactants [eg, polysorbate 80, HCO-50 (polyoxygenated castor oil). ethylene (50 mol) adduct), etc.], isotonic solutions containing saline, glucose and other adjuvants, etc., which can be used in combination with suitable solubilizers. As the oily medium, sesame oil, soybean oil, etc., which can be used in combination with solubilizers such as benzyl benzoate and benzyl alcohol, are used. The injection solution thus prepared can be filled into suitable ampoules.

Antibodies are typically formulated as described herein and in WO2011/085158, which is incorporated herein by reference in its entirety.

In various embodiments, the antibody is
- about 21 mM histidine,
- about 45 mM arginine,
- about 0.2% (w/v) polysorbate 20,
- administered as an aqueous buffer solution of about pH 6.0 containing - about 5% (w/v) sucrose, and - about 100 mg/mL to about 200 mg/mL antibody.

In another embodiment, the antibody is
- about 21 mM histidine,
- about 45 mM arginine,
- about 0.2% (w/v) polysorbate 20,
- administered as an aqueous buffer solution of about pH 6.0, containing about 5% (w/v) sucrose, and - at least about 130 mg/mL antibody.

In another embodiment, the antibody is
- about 21 mM histidine,
- about 45 mM arginine,
- about 0.2% (w/v) polysorbate 20,
- administered as an aqueous buffer solution of about pH 6.0 containing about 5% (w/v) sucrose, and - about 131.6 mg/mL antibody

In another embodiment, the antibody is
- about 21 mM histidine,
- about 45 mM arginine,
- about 0.2% (w/v) polysorbate 20,
- about 5% (w/v) sucrose; and - about pH 6.0 aqueous buffer solution containing about 175 mg/mL antibody.

In other embodiments, the antibody is
-21 mM histidine,
-45 mM arginine,
- 0.2% (w/v) polysorbate 20,
It is administered as an aqueous buffered solution at pH 6.0 containing -5% (w/v) sucrose and -100 mg/mL to 200 mg/mL of antibody.

In another embodiment, the antibody is
-21 mM histidine,
-45 mM arginine,
- 0.2% (w/v) polysorbate 20,
- 5% (w/v) sucrose, and - administered as an aqueous buffer solution at pH 6.0 containing at least 130 mg/mL of antibody.

In another embodiment, the antibody is
-21 mM histidine,
-45 mM arginine,
- 0.2% (w/v) polysorbate 20,
Administered as an aqueous buffer solution at pH 6.0 containing -5% (w/v) sucrose and -131.6 mg/mL antibody.

In another embodiment, the antibody is
-21 mM histidine,
-45 mM arginine,
- 0.2% (w/v) polysorbate 20,
Administered as an aqueous buffer solution at pH 6.0 containing -5% (w/v) sucrose; and -175 mg/mL antibody.

In various embodiments, the antibody comprises (i) histidine at a concentration of 25 mM to 100 mM; (ii) arginine at a concentration of 25 mM to 50 mM; (iii) sucrose in an amount of 3% to 10% w/v; ) as a stable pharmaceutical formulation comprising polysorbate 20 in an amount of 0.1% to 0.2%, the formulation having a pH of about 5.8, about 6.0, or about 6.2; After one month of storage at 45° C., at least 90% of native antibody is recovered as determined by particle size exclusion chromatography. In various embodiments, about 150 mg of antibody (eg, sarilumab) is administered to the subject.

In various embodiments, the antibody comprises (i) histidine at a concentration of about 10 mM to about 25 mM; (ii) arginine at a concentration of about 25 mM to about 50 mM; (iii) an amount of about 5% to about 10% w/v. of sucrose; and (iv) polysorbate in an amount of about 0.1% to about 0.2% w/v, wherein the formulation is about 5.8, about 6.0, or about Having a pH of 6.2 and after one month of storage at 45° C., at least 90% of the native antibody is recovered as determined by particle size exclusion chromatography. In various embodiments, about 150 mg of antibody (eg, sarilumab) is administered to the subject.

Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared in dosage form with unit doses suitable to suit the dosage of the active ingredient. Such dosage forms in unit dosage include, for example, tablets, pills, capsules, injections (ampoules), suppositories, and the like.

In various embodiments, an anti-IL-6R antibody (or pharmaceutical formulation comprising the antibody) can be administered to a patient using any acceptable device or mechanism. For example, administration can be accomplished using a syringe and needle, or using a reusable pen and/or autoinjector delivery device. Methods of the disclosure include the use of multiple reusable pen and/or autoinjector delivery devices to administer anti-IL-6R antibodies (or pharmaceutical formulations comprising antibodies). Examples of such devices include, but are not limited to, AUTOOPEN (Owen Mumford, Inc., Woodstock, UK), DISETRONIC pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75/25 pen, HUMALOG pen, HUMALIN 70 /30 pens (Eli Lilly and Co., Indianapolis, IN), NOVOPEN I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR (Novo Nordisk, Copenhagen, Denmark), BD pens (Becton Dickinson, Frankins, Frankins) NJ), OPTIPEN, OPTIPEN PRO, OPTIPEN STARLET, and OPTICLIK (Sanofi-Aventis, Frankfurt, Germany). Non-limiting examples of disposable pen and/or auto-injector delivery devices that find use in subcutaneous delivery of the pharmaceutical compositions of the present disclosure include, but are not limited to, the SOLOSTAR pen (Sanofi-Aventis), FLEXPEN (Novo Nordisk), and KWIKPEN (Eli Lilly), SURECLICK Autoinjector (Amgen, Thousand Oaks, Calif.), PENLET (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA Pen (AbbVie Inc., North , IL).

In various embodiments, the antibody is administered in a pre-filled syringe. In various embodiments, antibodies are administered in a pre-filled syringe that includes a safety system. For example, safety systems prevent accidental needlestick injuries. In various embodiments, the antibody is administered in a pre-filled syringe that includes an ERIS safety system (West Pharmaceutical Services Inc.). See also US Pat. Nos. 5,215,534 and 9,248,242, which are hereby incorporated by reference in their entireties.

In various embodiments, antibodies are administered using an auto-injector. In various embodiments, antibodies are administered using an auto-injector featuring PUSHCLICK technology (SHL Group). In various embodiments, an auto-injector is a device that includes a syringe that allows administration of a dose of a composition and/or antibody to a subject. See also US Pat. Nos. 9,427,531 and 9,566,395, which are hereby incorporated by reference in their entireties.

The use of microinfusors to deliver anti-IL-6R antibodies (or pharmaceutical formulations containing antibodies) to patients is also contemplated herein. As used herein, the term "microinfuser" refers to a large volume (e.g., about 2.5 mL or more) for an extended period of time (e.g., about 10, 15, 20, 25, 30 minutes or more). above) is a subcutaneous delivery device designed to slowly administer the therapeutic formulation. For example, US Pat. No. 6,629,949; US Pat. No. 6,659,982; and Meehan et al., J. Am. See Controlled Release, 46:107-116 (1996). Microinfusors are particularly useful for delivery of high concentrations (eg, about 100, 125, 150, 175, 200 mg/mL or more) and/or large doses of therapeutic proteins contained within viscous solutions.

In various embodiments, an inadequate response to prior therapy refers to a subject whose pain is not adequately controlled after receiving the prior therapy at a representative maximum tolerated dose. In certain embodiments, an inadequate response to prior therapy refers to subjects with moderate or high disease activity and poor prognostic characteristics despite prior therapy. In various embodiments, an inadequate response to prior therapy has pain symptoms that have not improved or that have worsened despite prior therapy (e.g., any of the symptoms listed herein) Point to target.

Patient Population As used herein, "subject" means a human subject or human patient.

Antibodies as described herein, in various embodiments, are administered to a subject who has rheumatoid arthritis and is suffering from intolerable pain (UP), wherein UP in the subject is inflammatory control ( IC) or UP within a subject has a strict RP. In various embodiments, the subject has UP and rheumatoid arthritis. In various embodiments, the subject has UP-IC and rheumatoid arthritis. In various embodiments, the subject has UP strict RP and rheumatoid arthritis. In various embodiments, the subject has previously been treated for rheumatoid arthritis by administering one or more DMARDs different from the IL-6R antibody without success.

Subjects considered "treated but ineffective" by their attending physician are, in various embodiments, subjects who are found to be intolerant to one or more DMARDs tested by their physician and/or subjects who have shown an inadequate response to one or more DMARDs tested by a physician, typically to whom one or more DMARDs have previously been administered Nonetheless, subjects are still considered by physicians to exhibit or have UP.

In various embodiments, the rheumatoid arthritis subject is
- at least 6 of 66 swollen joints and 8 of 68 tender joints, as measured by a physician in a representative swollen and tender joint count quantitative test;
- High-sensitivity C-reactive protein (hs-CRP) ≧8 mg/L or ESR ≧28 mM/H
-DAS28ESR>5.1
have

In various embodiments, a subject who has previously been treated for rheumatoid arthritis by administering at least one DMARD different from the antibody without success has never been treated for UP by administering a DMARD. A subject who received it but had no effect. In various embodiments, the DMARD is selected from the group consisting of methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine. In various embodiments the DMARD is methotrexate. In various embodiments the DMARD is a TNF-α antagonist. In various embodiments, the DMARD is adalimumab.

In various embodiments, a subject who has previously been treated for UP by administering one or more DMARDs that are different from the antibody without success responds poorly or is intolerant to methotrexate. It is a subject that was.

In various embodiments, for subjects who have previously been treated for UP by administering one or more DMARDs that are different from the IL-6R antibody with no effect, one or more The DMARD is no longer administered to the subject, and in various embodiments the IL-6R antibody is administered alone in monotherapy to the subject.

In various embodiments, the subject is intolerant to DMARDs due to one or more physical reactions, conditions, or symptoms resulting from treatment with DMARDs. Physical reactions, conditions, or symptoms that include allergies, pain, nausea, diarrhea, azotemia, gastric bleeding, intestinal bleeding, stomatitis, thrombocytopenia, small bowel perforation, bacterial infections, gum or oral cavity inflammation, Inflammation of the stomach or intestinal lining, bacterial sepsis, gastric ulcers, intestinal ulcers, cutaneous sun sensitivity, dizziness, anorexia, lack of energy, and vomiting can be mentioned. In certain embodiments, intolerance can be determined by a subject or by a health care professional upon examination of the subject. In various embodiments, the DMARD is selected from the group consisting of methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine. In certain embodiments, the DMARD is methotrexate.

In certain embodiments, the present disclosure provides administering to the subject one or more additional therapeutic agents in combination with the IL-6R antibody. As used herein, the phrase “in combination with” means that the additional therapeutic agent is administered before, after, or at the same time as the pharmaceutical composition comprising the IL-6R antibody. In certain embodiments, a subject is administered an antibody with a DMARD and/or a TNF-α antagonist.

All publications mentioned herein are hereby incorporated by reference in their entirety for all purposes.

Odds ratios for intolerable pain (UP) and intolerable pain despite refractory pain control (RC) or inflammation control-strict (RP-strict) in three randomized controlled clinical trials (RCTs) of sarilumab. Sarilumab was previously observed to improve pain in RA patients in three RCTs of sarilumab administered subcutaneously at doses of 150 mg or 200 mg every two weeks compared to therapy.

Across all three trials (baseline characteristics by treatment arm were similar in each trial, see Table 1), sarilumab dosed at 150 mg and 200 mg resulted in better inflammation control and UP rate compared to comparators. associated with a decline (see FIGS. 2A-2C) and decreased odds of UP compared to comparators (nominal p<0.05, see FIGS. 1A-1C).

Across all 3 RCTs, sarilumab 150 mg and 200 mg had lower odds of intolerable pain when compared to comparators using OR (Fig. 1A):
MOBILITY, week 24, sarilumab 150 mg: 0.46 [0.34, 0.61]; sarilumab 200 mg: 0.39 [0.29, 0.52]) and MOBILITY, week 52 150 mg: 0.40 [0.30, 0.54]; sarilumab 200 mg: 0.39 [0.30, 0.53]; all nominal p<0.001
TARGET, sarilumab 150 mg: 0.41 [0.26, 0.65]; sarilumab 200 mg: 0.44 [0.28, 0.69]); nominal p < 0.05
MONARCH, sarilumab 200 mg: 0.54 [0.36, 0.81]; nominal p<0.05

Data from the MOBILITY trial showed that when compared to placebo, both sarilumab doses increased at week 24 (sarilumab 150 mg: 0.60 [0.38, 0.93]; sarilumab 200 mg: 0.57 [0.37, 0.87]), and at week 52 (sarilumab 150 mg: 0.64 [0.37, 1.02]; sarilumab 200 mg: 0.62 [0.37, 1.02]). Odds of RP nevertheless, as well as RP-strict at week 52 (sarilumab 150 mg: 0.41 [0.19, 0.90]; (MOBILITY trial) odds (nominal p<0.05) were clearly reduced (Fig. 1C). Data from the TARGET trial revealed that sarilumab 150 mg reduced the odds of RP-strict (p<0.05) at week 24 (0.05 [0.01; 0.39]). rice field. Higher pain levels were associated with worse levels of FACIT-fatigue, HAQ, SJC, and TJC (all p<0.001), and UP was clinically significant in all these outcomes. There was generally moderate concordance with the probability of achieving a response with marginal differences (κ coefficient values 0.41-0.60).

There was no significant difference in the odds of intractable pain for sarilumab 200 mg or adalimumab 40 mg compared to placebo in TARGET and MONARCH, respectively.

Overall study design and plan:
Post-hoc Analysis of Three Randomized Controlled Clinical Trials (RCTs) Data from three phase III RCTs were collected to determine whether sarilumab contributes to pain improvement in subjects with RA. In the MOBILITY trial [NCT01061736], sarilumab 150 mg or 200 mg was administered to patients compared to placebo once every two weeks for 24 or 52 weeks along with conventional DMARDs; and in the MONARCH trial [NCT02332590], patients who received sarilumab monotherapy 200 mg once every two weeks received adalimumab monotherapy 40 mg once every two weeks. compared with patients who received Pain Outcomes: UP (based on patient's Acceptable Symptom Status [PASS] with visual analog scale threshold for pain >40 mm [0-100]), RP (UP C-reactive protein <10 mg/mL), and RP-strict (RP with swollen joint count ≤1), and association between pain and fatigue (FACIT-fatigue), and disease activity (Health Assessment Questionnaire [HAQ], SJC, and tender joint A post-hoc analysis was performed for the odds ratio (OR) of the number [TJC]). Population demographics and clinical characteristics for each trial are outlined in Table 1.

Claims (87)

A method of treating excruciating pain (UP) in a subject in need thereof having rheumatoid arthritis comprising administering a therapeutically effective dose of an antibody that specifically binds to the IL-6 receptor, wherein the antibody is , a heavy chain variable region comprising the complementarity determining regions HCDR1, HCDR2, and HCDR3, and a light chain variable region comprising the complementarity determining regions LCDR1, LCDR2, and LCDR3;
(a) HCDR1 comprises the amino acid sequence of SEQ ID NO:3;
(b) HCDR2 comprises the amino acid sequence of SEQ ID NO:4;
(c) HCDR3 comprises the amino acid sequence of SEQ ID NO:5;
(d) LCDR1 comprises the amino acid sequence of SEQ ID NO:6;
(e) LCDR2 comprises the amino acid sequence of SEQ ID NO:7; and (f) LCDR3 comprises the amino acid sequence of SEQ ID NO:8. 2. The method of claim 1, wherein the antibody that specifically binds to the IL-6 receptor comprises the heavy chain variable region sequence of SEQ ID NO:1 and the light chain variable region sequence of SEQ ID NO:2. 2. The method of claim 1, wherein the subject has refractory pain (RP). 2. The method of claim 1, wherein the subject has strict RP. 2. The method of claim 1, wherein the subject experiences a reduction to less than 40 mm on a visual analogue scale (VAS) after 24 weeks of treatment. 2. The method of claim 1, wherein the subject experiences a reduction in VAS to less than 40 mm after 52 weeks of treatment. 2. The method of claim 1, wherein the subject has a Disease Activity Score (DAS) of 3.2-5.1. 2. The method of claim 1, wherein the subject has a DAS greater than 5.1. 9. The method of any one of claims 1-8, wherein the antibody is administered subcutaneously. 10. The method of any one of claims 1-9, wherein the subject is administered a dose of about 150 mg or about 200 mg of the antibody. 11. The method of any one of claims 1-10, wherein the antibody is administered to the subject at least once every two weeks. 12. The method of any one of claims 1-11, wherein inflammation within the subject is reduced by a disease-modifying anti-rheumatic drug (DMARD). 13. The method of claim 12, wherein the DMARD is a sDMARD. 13. The method of claim 12, wherein the DMARD is methotrexate. 15. The method of claim 14, wherein the subject has moderately to severely active rheumatoid arthritis. 16. The method of any one of claims 1-15, wherein the subject is not administered any other DMARD during the course of administration of the antibody. 16. The method of any one of claims 1-15, wherein the subject is also administered one or more additional DMARDs along with the antibody. 18. The method of claim 17, wherein the one or more additional DMARDs comprises methotrexate. 18. The method of Claim 17, wherein the one or more additional DMARDs comprise a TNF antagonist. 20. The method of claim 19, wherein the TNF antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. 21. The method of any one of claims 1-20, wherein the subject has previously been treated for rheumatoid arthritis by administering at least one DMARD different from the antibody without success. 22. The method of claim 21, wherein the DMARD is methotrexate. 22. The method of Claim 21, wherein the DMARD is a TNF antagonist. 24. The method of claim 23, wherein the TNF antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. of claims 1-24, wherein the subject is intolerant to one or more DMARDs, or the subject is considered an unsuitable candidate for continued treatment with one or more DMARDs A method according to any one of paragraphs. 25. The method of any one of claims 1-24, wherein the subject had an inadequate response to one or more DMARDs. 27. The method of claim 25 or 26, wherein the DMARD is methotrexate. 27. The method of claim 25 or 26, wherein the DMARD is a TNF antagonist. 29. The method of claim 28, wherein the TNF antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. A method of treating intolerable pain (UP) in a subject in need thereof, comprising:
(i) selecting a subject with rheumatoid arthritis and UP;
(ii) administering to the subject a therapeutically effective dose of an antibody that specifically binds to the IL-6 receptor, wherein the antibody comprises a heavy chain variable comprising complementarity determining regions HCDR1, HCDR2, and HCDR3 a light chain variable region comprising the regions and the complementarity determining regions LCDR1, LCDR2, and LCDR3:
(a) HCDR1 comprises the amino acid sequence of SEQ ID NO:3;
(b) HCDR2 comprises the amino acid sequence of SEQ ID NO:4;
(c) HCDR3 comprises the amino acid sequence of SEQ ID NO:5;
(d) LCDR1 comprises the amino acid sequence of SEQ ID NO:6;
(e) LCDR2 comprises the amino acid sequence of SEQ ID NO:7; and (f) LCDR3 comprises the amino acid sequence of SEQ ID NO:8. 31. The method of claim 30, wherein the antibody that specifically binds IL-6 receptor comprises the heavy chain variable region sequence of SEQ ID NO:1 and the light chain variable region sequence of SEQ ID NO:2. 31. The method of claim 30, wherein the subject has refractory pain (RP). 31. The method of claim 30, wherein the subject has strict RP. 31. The method of claim 30, wherein the subject experiences a reduction to less than 40 mm on a visual analogue scale (VAS) after 24 weeks of treatment. 31. The method of claim 30, wherein the subject experiences a reduction in VAS to less than 40 mm after 52 weeks of treatment. 31. The method of claim 30, wherein the subject has a Disease Activity Score (DAS) of 3.2-5.1. 31. The method of claim 30, wherein the subject has a DAS greater than 5.1. 38. The method of any one of claims 30-37, wherein the antibody is administered subcutaneously. The method of any one of claims 30-38, wherein the subject is administered a dose of about 150 mg or about 200 mg of the antibody. 40. The method of any one of claims 30-39, wherein the antibody is administered to the subject at least once every two weeks. 31. The method of any one of claims 30-30, wherein inflammation within the subject is reduced by a disease modifying antirheumatic drug (DMARD). 42. The method of claim 41, wherein the DMARD is a sDMARD. 42. The method of claim 41, wherein the DMARD is methotrexate. 31. The method of claim 30, wherein the subject has moderately to severely active rheumatoid arthritis. 45. The method of any one of claims 30-44, wherein the subject is not administered any other DMARD during the course of administration of the antibody. 46. The method of any one of claims 30-45, wherein the subject is also administered one or more additional DMARDs along with the antibody. 47. The method of claim 46, wherein the one or more additional DMARDs comprises methotrexate. 47. The method of Claim 46, wherein the one or more additional DMARDs comprise a TNF antagonist. 49. The method of claim 48, wherein the TNF antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. 50. The method of any one of claims 30-49, wherein the subject has previously been treated for rheumatoid arthritis by administering at least one DMARD different from the antibody without success. 51. The method of claim 50, wherein the DMARD is methotrexate. 51. The method of Claim 50, wherein the DMARD is a TNF antagonist. 53. The method of claim 52, wherein the TNF antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. of claims 30-53, wherein the subject is intolerant to one or more DMARDs, or the subject is considered an unsuitable candidate for continued treatment with one or more DMARDs A method according to any one of paragraphs. 55. The method of any one of claims 30-54, wherein the subject had an inadequate response to one or more DMARDs. 56. The method of claim 54 or 55, wherein the DMARD is methotrexate. 56. The method of claim 54 or 55, wherein the DMARD is a TNF antagonist. 58. The method of claim 57, wherein the TNF antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. An antibody for use in treating excruciating pain in a patient in need thereof having rheumatoid arthritis, said antibody specifically binding to the IL-6 receptor and comprising complementarity determining regions HCDR1, HCDR2 and HCDR3 comprising a heavy chain variable region and a light chain variable region comprising complementarity determining regions LCDR1, LCDR2, and LCDR3:
(a) HCDR1 comprises the amino acid sequence of SEQ ID NO:3;
(b) HCDR2 comprises the amino acid sequence of SEQ ID NO:4;
(c) HCDR3 comprises the amino acid sequence of SEQ ID NO:5;
(d) LCDR1 comprises the amino acid sequence of SEQ ID NO:6;
(e) LCDR2 comprises the amino acid sequence of SEQ ID NO:7; and (f) LCDR3 comprises the amino acid sequence of SEQ ID NO:8. Antibody for use according to claim 59, wherein the antibody that specifically binds to the IL-6 receptor comprises the heavy chain variable region sequence of SEQ ID NO:1 and the light chain variable region sequence of SEQ ID NO:2. 60. An antibody for use according to claim 59, wherein the subject has refractory pain (RP). 60. Antibody for use according to claim 59, wherein the subject has a strict RP. 60. The antibody for use according to claim 59, wherein the subject experiences a reduction to less than 40 mm on the visual analogue scale (VAS) after 24 weeks of treatment. 60. The antibody for use according to claim 59, wherein the subject experiences a reduction in VAS to less than 40 mm after 52 weeks of treatment. Antibody for use according to claim 59, wherein the subject has a disease activity score (DAS) of 3.2 to 5.1. 60. An antibody for use according to claim 59, wherein the subject has a DAS greater than 5.1. Antibody for use according to any one of claims 59 to 66, wherein the antibody is administered subcutaneously. The antibody for use according to any one of claims 59-67, wherein the subject is administered a dose of about 150 mg or about 200 mg of the antibody. Antibody for use according to any one of claims 59 to 68, wherein the antibody is administered to the subject at least once every two weeks. Antibody for use according to any one of claims 59 to 69, wherein inflammation in the subject is reduced by a disease modifying anti-rheumatic drug (DMARD). 71. The antibody for use according to claim 70, wherein the DMARD is a sDMARD. 71. An antibody for use according to claim 70, wherein the DMARD is methotrexate. Antibody for use according to any one of claims 59 to 72, wherein the subject has moderately to severely active rheumatoid arthritis. Antibody for use according to any one of claims 59 to 73, wherein the subject is not administered any other DMARD during the course of administration of the antibody. The antibody for use according to any one of claims 59-73, wherein the subject is also administered one or more additional DMARDs with the antibody. 76. An antibody for use according to claim 75, wherein the one or more additional DMARDs comprises methotrexate. 76. Antibody for use according to claim 75, wherein the one or more additional DMARDs comprise a TNF antagonist. 78. The antibody for use according to claim 77, wherein the TNF antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. The antibody for use according to any one of claims 59 to 78, wherein the subject has previously been treated for rheumatoid arthritis by administering at least one DMARD different from the antibody without success. . 80. An antibody for use according to claim 79, wherein the DMARD is methotrexate. 80. Antibody for use according to claim 79, wherein the DMARD is a TNF antagonist. 82. The antibody for use according to claim 81, wherein the TNF antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. of claims 59-82, wherein the subject is intolerant to one or more DMARDs, or the subject is considered an unsuitable candidate for continued treatment with one or more DMARDs An antibody for use according to any one of claims. The antibody for use according to any one of claims 59-82, wherein the subject had an inadequate response to one or more DMARDs. 85. Antibody for use according to claim 83 or 84, wherein the DMARD is methotrexate. 85. Antibody for use according to claim 83 or 84, wherein the DMARD is a TNF antagonist. 87. The antibody for use according to claim 86, wherein the TNF antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol.

Images